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International Journal of Medical Microbiology xxx (2013) xxxxxx
Contents lists available at ScienceDirect
International Journal of Medical Microbiology

journal homepage: www.elsevier.com/locate/ijmm
Mini Review
Hostpathogen interactions in epidermolysis bullosa patients

colonized with Staphylococcus aureus
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Magdalena M. van der Kooi-Pol a , Jos C. Duipmans b , Marcel F. Jonkman b ,

Jan Maarten van Dijl a,
a
Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen,
The Netherlands
b
Department of Dermatology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The
Netherlands
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a r t i c l e
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a b s t r a c t
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Article history:
Available online xxx
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Keywords:
Epidermolysis bullosa
Staphylococcus aureus
Wound
Colonization
Patients with the genetic blistering disease epidermolysis bullosa (EB) often have chronic wounds that
can become colonized by different bacteria, especially the opportunistic pathogen Staphylococcus aureus.
We therefore determined the S. aureus colonization rates in EB patients from the Netherlands by collecting swabs from their anterior nares, throats and wounds. Within a period of 2 years, more than
90% of the sampled chronic wounds of EB patients were found to be colonized by S. aureus. Molecular
typing revealed that EB patients were not colonized by a single S. aureus type. Rather the S. aureus population structure in the sampled EB patients mirrored the local S. aureus population structure within the
Netherlands. Furthermore, multiple types of S. aureus were found in close proximity to each other within
individual chronic wounds, indicating that these S. aureus types are not mutually exclusive. Over time,
strong uctuations in the S. aureus types sampled from individual EB patients were observed. This high
exposure to different S. aureus types is apparently reected by high plasma levels of antistaphylococcal
IgGs, especially in patients carrying multiple S. aureus types. It remains to be determined to what extent
this strong immune response protects EB patients against serious staphylococcal infections. Lastly, further research is needed to dene the impact of staphylococcal colonization of chronic wounds on the
development, exacerbation and healing of such wounds in patients with EB.
2013 Published by Elsevier GmbH.
Staphylococcus aureus harmless commensal or dangerous

pathogen?
Staphylococcus aureus is a Gram-positive bacterium frequently
found in the nasal cavity of humans and several animal species
(Wertheim et al., 2005). In humans, the anterior nares are the most
frequent carriage sites for S. aureus. Other known carriage sites
include the skin, perineum, pharynx as well as the gastrointestinal tract, vagina and axillae (Mermel et al., 2011; Lauderdale et al.,
2010). The colonization rate in the healthy human population is
established at about 30% (Wertheim et al., 2005; Kluytmans et al.,
1997). However, if the primary barrier function of the skin is disrupted, or if the immune system is compromised, S. aureus can
become a dangerous pathogen that has the potential to invade
Corresponding author at: Department of Medical Microbiology, University of

Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, HPC
EB80, 9700 RB Groningen, The Netherlands. Tel.: +31 50 3615187;
fax: +31 50 3619105.
E-mail address: J.M.van.Dijl01@umcg.nl (J.M. van Dijl).
almost all tissues and organs causing a broad range of diseases

(Lowy, 1998). These can vary from mild skin infections, such as
impetigo, to life-threatening systemic infections (e.g. pneumonia,
meningitis and sepsis) (Zervos et al., 2012; Forsblom et al., 2011;
Aguilar et al., 2010; Corrah et al., 2011). Not only the diseases that
this pathogen can cause are alarming, but also its high propensity to
acquire resistance to antibiotics (Lowy, 2003). In the pre-antibiotic
era, the mortality of patients with S. aureus bacteremia exceeded
80%, and over 70% developed metastatic infections (Skinner, 1941).
The prognosis of patients with S. aureus infections improved drastically since the introduction of penicillin in the early 1940s.
However, already a few years later, the rst S. aureus strains resistant against penicillin emerged in hospitals (Rammelkamp and
Maxon, 1942). In the 1960s, a new semi-synthetic antibiotic
methicillin was introduced for treatment of staphylococcal infections. Also in this case, the rst methicillin resistant S. aureus strains
(MRSA) were already observed within a period of two years after
the introduction of this antibiotic (Lowy, 2003). The rst infections caused by MRSA used to be associated with hospitalized
patients. This phenomenon is generally referred to as hospitalacquired MRSA (HA-MRSA). However, in recent years, the spread
1438-4221/$ see front matter 2013 Published by Elsevier GmbH.

http://dx.doi.org/10.1016/j.ijmm.2013.11.012
Please cite this article in press as: van der Kooi-Pol, M.M., et al., Hostpathogen interactions in epidermolysis bullosa patients colonized with
Staphylococcus aureus. Int. J. Med. Microbiol. (2013), http://dx.doi.org/10.1016/j.ijmm.2013.11.012
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Fig. 1. Chronic wounds of patients with epidermolysis bullosa. The images show typical examples of chronic wounds of patients with EB as included in our studies on
staphylococcal wound colonization. Specically, these patients were diagnosed with: (A) Herlitz-type junctional epidermolysis bullosa (JEB-H); (B) severe generalized
recessive dystrophic epidermolysis bullosa (RDEB); (C and D) non-Herlitz-type junctional epidermolysis bullosa (JEB-nH), or (E) Dowling-Meara type epidermolysis bullosa
simplex (EBS-DM).
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of so-called community-acquired MRSA (CA-MRSA) strains has laid

an additional burden on the healthcare system (Saravolatz et al.,
1982; Mera et al., 2011). In contrast to HA-MRSA, the CA-MRSA lineages easily spread within the young and healthy community, and
they have now entered into hospitals causing nosocomial infections with even higher mortality rates than the hospital-acquired
strains (Patel et al., 2007; Moore et al., 2009). This focuses attention on the risks of severe staphylococcal infections for frail and
immune-compromised patients, or patients whose primary barrier function of the skin is impaired. The present review addresses
the S. aureus colonization of patients with the genetic blistering
disease epidermolysis bullosa (EB), who often suffer from large
chronic wounds that are readily colonized by staphylococci and a
few other microbes, such as Streptococcus species, and Pseudomonas
aeruginosa (Brandling-Bennett and Morel, 2010). For the purpose
of the studies reviewed here, EB patients with chronic wounds are
dened as those patients who have multiple non-healing wounds
over periods of more than 3 months (van der Kooi-Pol et al., 2012).
By contrast, EB patients without chronic wounds have relatively
few wounds that heal in shorter periods of time.
Epidermolysis bullosa
S. aureus infections are usually limited by the primary barriers of the skin and mucosa, as well as the innate and adaptive
immune responses of healthy individuals. However, the situation
is different in patients where these defenses are compromised.
Consequently, such patients may suffer from colonization and
infection by S. aureus. This has been extensively studied in patients
with cystic brosis or atopic dermatitis (Johannessen et al., 2012;
Callaghan and McClean, 2012; Goss and Muhlebach, 2011; BalmaMena et al., 2011; Kahl, 2010). In other groups of patients with
defective barriers, the interactions with S. aureus have been studied to lesser extents. One of these diseases is EB, which refers
to a group of inherited mechano-bullous disorders. Patients with
EB develop blisters as a consequence of trivial mechanical trauma
(Marinkovich, 1999; Fine and Hintner, 2009). The fragility of their
skin is due to defects in structural proteins within the epidermis
and at the epidermaldermal junction. Four major EB subtypes can
be distinguished based on the ultrastructural characteristics of blistering. EB simplex (EBS) is characterized by cleavage of basal cells
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within the epidermis. In junctional EB (JEB), subepidermal cleavage

occurs between the lamina densa and the basal cells. The Herlitz
type JEB (JEB-H) which is rarer and more severe than non-Herlitz
type JEB (JEB-nH), is caused by null mutations in the genes for
laminin-332, an important trimeric adhesion protein in the epidermal basement membrane (Yuen et al., 2012). In the absence
of laminin-332, the skin is prone to generalized painful blistering with persistent erosions and granulation tissue formation (Kho
et al., 2010). In dystrophic EB (DEB) the cleavage occurs below
the lamina densa. The so-called Kindler syndrome is characterized by mixed cleavage planes through the skin (Fine et al., 2008a).
Accordingly, a precise diagnosis of the type of EB is based on biopsies for electron microscopic analysis and immunouorescence
antigenic mapping (Pohla-Gubo et al., 2010; Eady and DoppingHepenstal, 2010). Furthermore, through sequence analysis the
precise mutation responsible for the disease can be determined,
which is important for conrmation of the diagnosis (Castiglia and
Zambruno, 2010). The overall world-wide EB prevalence data suggest that there is no gender, racial, or geographical predisposition
for EB (Sarkar et al., 2011). In the United States of America (USA), the
incidence and prevalence of EB have been estimated at 19 per million live births and 8 per million inhabitants, respectively (Fine,
2010). In the Netherlands, the incidence of EB is 100 new cases per
million live births, and the prevalence is 45 patients per million
inhabitants. Of these patients, 40% have been diagnosed with EBS,
25% with JEB, 35% with DEB and 0.4% with Kindler syndrome
(Jonkman et al., 2003). Depending on the type of EB, the symptoms
can vary widely in severity, ranging from minor to severe blistering
of the skin (Fig. 1), and even to a lethal form involving other organs
(Schober-Flores, 1999). In view of this large variation in symptoms,
it is conceivable that the clinically milder forms of EB have so far
remained underestimated (Sarkar et al., 2011).
Bacterial wound colonization

The ulceration of the skin in patients with EB leads to the development of wounds that become colonized by different bacteria, S.
aureus in particular (Brandling-Bennett and Morel, 2010; Mellerio,
2010). In general, four different stages can be distinguished in the
bacterial presence in wounds, namely contamination, colonization,
critical colonization and infection (Edwards and Harding, 2004)
(Fig. 2). Importantly, all chronic wounds should be considered as
being contaminated. In this case, mostly non-replicating microorganisms are present within a wound or on the wound surface
(Dow et al., 1999). The host defenses are usually capable of clearing
such contaminants and, consequently, they do not interfere with
wound healing. Colonization is dened by the presence of replicating microorganisms adhering to a wound in the absence of tissue
damage (Dow et al., 1999). Critical colonization refers to the transition state between colonization and invasive wound infection.
This is represented by conditions where the bacterial bio-burden
in the wound reaches levels that interfere with healing, while the
typical signs and symptoms of infection are not produced (Schultz
et al., 2003). Whether the colonizing organism invades the tissue
depends on a number of microbe-host interactions, such as the
amount of bacteria per gram tissue, virulence and pathogenicity
of the respective bacteria and proper innate and adaptive immune
responses of the host (Wysocki, 2002). Wound infection is characterized by the presence of replicating micro-organisms within
a wound with subsequent host injury (Dow et al., 1999). Typical
symptoms of wound infection include erythema, warmth, swelling,
pain, odor and purulent drainage (Lipsky et al., 2012; Raa and
Tredget, 2011). Notably, wound infections that are not adequately
treated have a potential to progress into systemic infections and
even sepsis (Raa and Tredget, 2011).
Fig. 2. Schematic representation of the bacterial presence in wounds. The bacterial

presence in wounds can be categorized by four different conditions: contamination,
colonization, critical colonization and infection. Ultimately, this can lead to invasive
diseases, such as sepsis.
Figure adapted from Edwards and Harding (2004).
Colonization of patients with EB

To determine how the absence of the protective skin barrier
predisposes EB patients for colonization by S. aureus, we recently
investigated the nasal, throat and wound colonization rates in a
cohort of 62 EB patients from the Netherlands (van der Kooi-Pol
et al., 2012, 2013a). Over a period of about 2 years, this revealed an
unexpectedly high rate of colonization not only in their wounds,
but also in the anterior nares and throat (Fig. 3; van der KooiPol et al., 2012, 2013a). Specically, the nasal colonization rates
determined for EB patients (62% or 75% for patients without or
with chronic wounds; Fig. 3) were substantially higher than those
measured for healthy individuals (2537%) (Wertheim et al., 2005;
Kluytmans et al., 1997), or healthcare workers who met the sampled EB patients at regular intervals (39%) (van der Kooi-Pol et al.,
2012). Furthermore, while the S. aureus throat colonization in EB
patients without chronic wounds (26%) was similar to that of the
afore-mentioned healthcare workers (23%), it was substantially
Fig. 3. Frequency of S. aureus detected in patients with EB. A distinction was made
between EB patients without chronic wounds (white bars) and EB patients with
chronic wounds (black bars). The statistical signicance of observed differences was
assessed using two-tailed independent student t-tests. Differences with P-values of
0.05 are marked with one star (*), and differences with P-values of 0.001 are
marked with two stars (**).
Numbers were derived from van der Kooi-Pol et al. (2012, 2013a).
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higher in EB patients with chronic wounds (55%) (van der KooiPol et al., 2012). Importantly, the wounds of patients with EB were
found to be highly colonized by S. aureus as, over time, this bacterium was encountered in the wounds of 92% of the EB patients
with chronic wounds, and in the wounds of 69% of the patients
without chronic wounds (Fig. 3) (Brandling-Bennett and Morel,
2010; van der Kooi-Pol et al., 2012). Although this has not yet been
demonstrated unambiguously, it seems likely that the high rate
of S. aureus wound colonization contributes to the development
of chronic wounds in patients with EB (Kluytmans et al., 1997;
Mellerio, 2010; Madsen et al., 1996; Grimble et al., 2001). In addition, it may predispose EB patients to life-threatening infections.
This view is underscored by the observation that sepsis is a leading cause of death amongst infants with EB in the USA. Specically,
septicemia was associated with a cumulative risk of death for 17.5%
of the patients with JEB-H by the age of 8 years, and for 24.2% of the
patients with JEB-nH by the age of 15 years (Fine et al., 2008b). In
this context it should be noted that patients with JEB-H most often
die during childhood. Possibly, the high susceptibility of patients
with JEB-H to staphylococcal wound infections relates to the high
numbers of recurrent skin erosions. These are less prominent or
absent from the wounds of patients with other types of EB. This
may also explain why patients with other types of EB seem to be
less susceptible for invasive infections by S. aureus, despite high
colonization rates (Yuen et al., 2011).
Interestingly, the molecular typing of S. aureus isolates by
Multiple-Locus Variable number tandem repeat Analysis (MLVA)
(Schouls et al., 2009) and spa-typing (Harmsen et al., 2003) revealed
that the colonization of EB patients is not limited to specic genetic
lineages of S. aureus (Fig. 4) (van der Kooi-Pol et al., 2012). Furthermore, autoinoculation of staphylococci between the upper
respiratory tract and wounds of EB patients was shown to occur
frequently (van der Kooi-Pol et al., 2012). Together, these ndings
imply that the colonization of EB patients by S. aureus is a random
process, a view that is clearly supported by our spa-typing analyses, which showed that most of the identied S. aureus spa-types
belong to the most predominant spa-types in the areas of residence of the respective EB patients (van der Kooi-Pol et al., 2012;
Grundmann et al., 2010). Thus, the S. aureus population structure in
EB patients appears to mirror the local S. aureus population structure in the Netherlands. It was also found that EB patients with
chronic wounds were colonized by up to six different S. aureus
types at one particular time point of sampling (van der Kooi-Pol
et al., 2012, 2013a,b). Notably, the comparison of S. aureus isolates
from EB patients over a period of 2 years showed that 58.3% of
the patients with chronic wounds and 43.5% of the patients without chronic wounds carried alternating S. aureus types over time.
In 8.7% of the patients without chronic wounds, a different MLVA
type was encountered in each sampling round. Merely 42.5% of
all sampled patients carried the same S. aureus type over the 2year sampling period. Altogether, these observations showed that
the included EB patients were continuously challenged by different S. aureus types, and that the S. aureus population carried by
these patients was subject to rapid changes. This conclusion was
underscored by studies in which the chronic wounds of EB patients
were investigated by replica-plating of used bandages and subsequent typing of S. aureus isolates (van der Kooi-Pol et al., 2013b).
In this case, an initial typing screen was performed by MultipleLocus Variable number of tandem repeats Fingerprinting (MLVF)
(Sabat et al., 2012, 2013), which was then rened by MLVA and
spa-typing. This revealed that distinct S. aureus types formed microcolonies in the wounds of EB patients. Notably, these microcolonies
were located in close proximity to each other, and sometimes even
overlapped (van der Kooi-Pol et al., 2013b). While some adjacent S.
aureus isolates belonged to closely related types, others belonged
to distinct molecular complexes. This implies that these different
S. aureus types are not mutually exclusive. Accordingly, we have

proposed that the general assumption that one individual is predominantly colonized by one type of S. aureus does not apply to
EB patients with chronic wounds. Here we envisage the following scenario for staphylococcal colonization. Presumably, the initial
colonization of an individual is a random process in which the
most frequently occurring S. aureus types in the individuals immediate environment have the highest chance to be transmitted to
this individual. Subsequently, the colonizing strain(s) will adapt to
the host and vice versa. Compared to patients with EB, a healthy
individual provides only a limited niche for staphylococci, which is
rapidly occupied by the best-adapted strain. Subsequently, it will be
more difcult for other S. aureus types to conquer the possible host
niches that are already occupied. This situation is very different in
EB patients where especially large chronic wounds substantially
increase the chances of successful transmission, the subsequent
colonization by multiple S. aureus types, and their adaptation to
the host. If so, this has important implications, not only for EB
patients, but also for other patients with chronic wounds that may
be colonized by multiple S. aureus types. Clearly, the presence of
different types of this opportunistic pathogen at high concentrations in chronic wounds could represent a serious risk for severe
staphylococcal infections.
Staphylococcal virulence factors

The virulence of S. aureus is caused by a broad range of cell
surface-exposed or secreted factors (Sibbald et al., 2006; Dreisbach
et al., 2011). These include surface-exposed proteins involved in
adherence and colonization of host tissues, surface-exposed factors involved in the inhibition of phagocytic engulfment (capsule
and protein A), invasins exported into the host environment to
promote the bacterial spread in invaded tissues (e.g. leukocidin,
kinases, and hyaluronidase), biochemical properties that enhance
staphylococcal survival in phagocytes (carotenoid and catalase production), immunological disguises (protein A, Sbi, coagulase, and
clotting factor), superantigens (egc and non-egc SAgs), toxins damaging the membrane of host cells (hemolysins and leukotoxin), and
determinants for inherent and acquired resistance to antimicrobial
agents (Sibbald et al., 2006). It is known that S. aureus populations carry a range of unique variants of these virulence factors,
and the variation in genes coding for surface proteins and immune
evasion factors has been shown to be lineage-specic (McCarthy
and Lindsay, 2010; Ziebandt et al., 2010). In particular, variations
were observed for genes encoding surface proteins. These may
be completely absent, or they may be truncated which can then
affect predicted functional domains (McCarthy and Lindsay, 2010).
The same applies also to genes encoding secreted proteins predicted to interact with the host immune system (McCarthy and
Lindsay, 2010). It has been suggested that the level of variation
in the latter genes may be less drastic than in genes encoding
surface proteins, and that their complete absence or truncation
may be less common (McCarthy and Lindsay, 2010). However, this
needs to be veried by the detailed analysis of larger numbers of
S. aureus isolates of different types and origin. Notably, variations
in cell surface-exposed and secreted proteins can also relate to different expression levels in different S. aureus lineages (Ziebandt
et al., 2010). The variations in the expression levels of virulence
genes may relate to differential activities of specic regulators.
One of the key regulators of virulence factor genes is the RNAIII,
which is responsible for their cell density-dependent expression
(Novick, 2003). In addition, at least 16 two-component regulatory
systems are to different extents involved in staphylococcal virulence (Gill et al., 2005). Strain-specic differences in gene regulation
may result in very different cell surface proteome (surfacome) and
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Fig. 4. General S. aureus population structure in the Netherlands. The minimal spanning tree was based on MLVA of 23,000 S. aureus isolates of which 90% were MRSA. S.
aureus isolates from the nose and/or throat of EB patients are marked by green circles. S. aureus isolates from the wounds of EB patients are marked by red circles. The size
of each circle is indicative for the number of S. aureus isolates with the respective MLVA type. The tree locations of S. aureus isolates from the upper respiratory tract (URT)
or chronic wounds (W) of an EB patient (no. 44) are indicated with arrows.
Reproduced from van der Kooi-Pol et al. (2012).
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exoproteome patterns as have been shown for S. aureus cells grown

in vitro (Dreisbach et al., 2010, 2011; Ziebandt et al., 2010).
Notably, changes in the expression of virulence factors seem
to relate to different host environments (Burian et al., 2010a,b;
Krishna and Miller, 2012; Loughman et al., 2009; Malachowa
et al., 2011). In nasally carried S. aureus cells, the genes encoding
the most important adhesion molecules (e.g. clfB, isdA, fnbA, atlA,
eap), immune-modulating factors (sak, chp, spa) and cell surface
remodeling factors (sceD, oatA, atlA) are highly expressed, while
genes encoding major toxins (hla, psm) are not detectably transcribed (Burian et al., 2010a,b). In contrast, in cutaneous abscesses,
genes encoding toxin components, such as lukS-PV, lukE, hlgB
and hla are up-regulated, while RNAIII, bsaB and spa expression
seem to be down-regulated (Loughman et al., 2009). In addition,
S. aureus incubated in human serum or blood up-regulates the
genes involved in iron and iron transport-associated molecules
(Malachowa et al., 2011). Taken together, it can be concluded
that S. aureus shows major adaptive responses to different host

environments by changing the expression of different groups of virulence factors. Consistent with this idea, specic adaptive immune
responses might be raised against different staphylococcal virulence factors, depending on the site of infection as well as the
colonizing or invading strain.
Antistaphylococcal immune responses in EB patients
The immune responses against S. aureus and different staphylococcal proteins have been studied extensively both in healthy
human individuals as well as patients with different diseases. Thus,
it was reported that the levels of antibodies directed against the
toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxin A (SEA) and ClfA and ClfB are signicantly higher in healthy
persistent carriers than in healthy non-carriers (Verkaik et al.,
2009). Anti-staphylococcal antibody levels were shown to increase
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Fig. 5. IgG responses of EB patients to staphylococcal antigens. (A) The IgG levels against 43 puried S. aureus antigens in sera of EB patients (red diamonds; n = 13) or
age-matched healthy controls (blue triangles; n = 14) were determined by Luminex assays. Median uorescence intensity (MFI) values are marked by color-coded bars. (B)
IgG levels against 43 S. aureus antigens in sera of EB patients colonized by multiple S. aureus MLVA types (red triangles; n = 5), or EB patients colonized by only one S. aureus
MLVA type (green diamonds; n = 7) were determined by Luminex assays. MFI values are marked with red and green bars.
Reproduced from van der Kooi-Pol et al. (2013a).
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strongly during the course of infection in patients with bacteremia

(Kolata et al., 2011; Verkaik et al., 2010; Lorenz et al., 2000). This
applied in particular to antibodies against IsaA, IsaB, the major
cold shock protein (CspA) and the phosphocarrier protein (Hpr)
(Lorenz et al., 2000). In addition, Kolata et al. have shown that during bacteremia caused by exogenous S. aureus strains (i.e. strains not
carried by the patient), there was an increase of immunoglobulins
G (IgG) binding to antigens from the invasive strain, but not the colonizing strain (Kolata et al., 2011). In patients with EB, signicantly
higher anti-staphylococcal IgG levels have been observed than in
individuals of an age-matched healthy control group (Fig. 5; van der
Kooi-Pol et al., 2013b). Specically, this applied to IgGs against nine
important virulence factors: the surface proteins IsdA and SasG,
the secreted proteins IsaA, SCIN, Nuc and LytM, and the superantigens (SAgs) SEM, SEN and SEO. Notably, the IsaA, SCIN, Nuc,
and LytM proteins are expressed by many S. aureus types (Ziebandt
et al., 2010). Also, the egc gene cluster-encoded SAgs SEM, SEN and
SEO are amongst the most prevalent SAgs of S. aureus (5266%)
(Holtfreter et al., 2007). Intriguingly, persistent carriers, bacteremia
patients and furunculosis patients were found to develop no, or
only low levels of antibodies against these SAgs (Burian et al., 2012;
Grumann et al., 2011; Holtfreter et al., 2011). This suggests that EB
patients are more signicantly challenged by egc SAgs than healthy
carriers and bacteremia or furunculosis patients. Also the carriage

of multiple S. aureus strains has an impact on anti-staphylococcal
IgG levels, as shown by the comparison of the IgG responses of EB
patients colonized by only one S. aureus MLVA type with EB patients
colonized by multiple S. aureus MLVA types. Interestingly, the highest antistaphylococcal IgG levels were observed in patients carrying
multiple S. aureus MLVA types. This was particularly evident for
IgGs against IsdA, LukD, HlgB, LytM, LukS, LukF and ETA. Additionally, a signicant correlation between anti-staphylococcal IgG
levels in serum, wound uid and sterile blister uid was detected in
samples from one EB patient (van der Kooi-Pol et al., 2013a). Altogether, these observations suggest that the high adaptive immune
responses of EB patients against S. aureus are directly or indirectly
due to the high colonization rates with very diverse S. aureus types.
In the rst place, these patients seem to be exposed to high concentrations of different staphylococcal antigens for the largest part of
their life. Secondly, as a consequence of the high-level colonization
by S. aureus, it seems likely that these patients experience multiple
invasive episodes that can elicit strong adaptive immune responses.
While there are currently no data available concerning possible cellular adaptive immune responses of EB patients against S. aureus,
the observed high anti-staphylococcal antibody levels suggest that
humoral adaptive immune responses could be important to combat
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invasive staphylococcal infections. Lastly, innate immune mechanisms may also be important for protecting EB patients against
severe staphylococcal infections, but this has not been investigated
so far.
Staphylococcal interference with wound healing
The healthy human skin is a fantastic barrier against infections by pathogenic microorganisms. When this barrier is breached
due to trauma or disease, bacteria from the skin surface and
environment are able to gain access to underlying tissues where
the physical characteristics favor wound colonization and infection. Staphylococcal wound colonization is frequently associated
with delayed wound healing (Manson et al., 1992; Madsen et al.,
1996). Intriguingly, the interference of S. aureus with woundhealing mechanisms is poorly understood and very little is known
about the respective in-patient hostpathogen interactions at
the molecular level (Madsen et al., 1996; Grimble et al., 2001).
Notably, negative effects of bacterial colonization on wound healing have been clearly established in animal models (Pastar et al.,
2013; Athanasopoulos et al., 2006; Roche et al., 2012). This has
revealed the polymicrobial nature of non-healing wounds where
the bacteria are predominantly present in the form of biolms
that are highly resistant to antimicrobial treatments. Any available
molecular data are exclusively derived from in vitro experiments
and animal models, where mainly the interactions between S.
aureus and P. aeruginosa were investigated (Pastar et al., 2013).
Recent studies in a porcine cutaneous wound model showed that
re-epithelialization was signicantly delayed by mixed-species
biolms possibly through suppression of keratinocyte growth factor 1 (Pastar et al., 2013). Furthermore, co-existence of S. aureus
and P. aeruginosa in cutaneous wounds was shown to result in
induced expression of particular staphylococcal virulence factors
that have been implicated in skin and wound colonization. However, it should be emphasized that these experiments were carried
out with one S. aureus strain only (Pastar et al., 2013), whereas
we know that the bacterial diversity in chronic wounds is enormous. Specically, recent studies identied a plethora of different
and evolving S. aureus types in the chronic wounds of patients with
EB (van der Kooi-Pol et al., 2012, 2013a,b).
At the molecular level, just one staphylococcal protein has been
implicated in the delay of wound healing, namely the extracellular
adherence protein (Eap) (Athanasopoulos et al., 2006; Joost et al.,
2009). In a mouse wound-healing model, Eap was shown to delay
wound closure due to its anti-inammatory and antiangiogenic
activities (Athanasopoulos et al., 2006). It has been shown that Eap
can interact with adhesion molecules, such as the endothelial intercellular adhesion molecule 1 as well as with adhesive proteins in the
extracellular matrix, thereby blocking integrin-mediated adhesive
and migratory interactions of both inammatory and endothelial
cells. In the presence of Eap, recruitment of inammatory cells to
the wound site as well as neovascularization of the wound were
prevented. The delay of the wound healing due to the presence of
S. aureus was shown to be reversible when an isogenic Eap-decient
strain was used, demonstrating that inhibition of wound healing in
S. aureus-infected wounds can be at least in part attributed to Eap.
However, these ndings do not exclude the possibility that other S.
aureus factors may also be involved in delayed wound healing.
Conclusions and future perspectives
Altogether, it can be concluded that very little is known about
the essential processes that take place within S. aureus cells during the colonization of human wounds, and the same is true for
the host responses to staphylococcal wound colonization. More
importantly in the context of the present review, it is currently

not known to what extent S. aureus contributes to the initiation
of chronic wound development in patients with EB, or to what
extent S. aureus colonization interferes with chronic wound healing
in these patients. However, based on the extensive bacterial colonization of the wounds of patients with EB, we hypothesize that
bacteria play major roles in the development and exacerbation of
chronic wounds, and that the colonizing bacteria interfere significantly with wound healing. Therefore, key objectives for future
research in this area should be to dene (i) the precise mechanisms of bacterial wound colonization in patients with EB and (ii)
the essential interactions between colonizing bacteria and patients
with EB. This will pinpoint the Achilles heel(s) of bacteria growing
in wounds. Patients with EB may benet from such knowledge, as
it will potentially lead to informed strategies for effective prevention, care and/or healing of chronic wounds. Such new therapeutic
strategies are urgently needed, because the current approaches for
wound care do not effectively prevent or eliminate wound colonization by S. aureus and other bacteria.
Acknowledgements
The authors thank the anonymous patients with EB from the
Dutch Epidermolysis Bullosa Registry and healthcare workers from
the Department of Dermatology at the UMCG for their continuous
support. M.M.v.d.K.-P. and J.M.v.D. were in parts supported by the
CEU project LSHG-CT-2006-037469 and the Top Institute Pharma
projects T4-213 and T4-502. J.C.D. and M.F.J. were supported by the
Dutch Buttery Child Foundation.
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ARTICLE IN PRESS

International Journal of Medical Microbiology xxx (2013) xxxxxx

Contents lists available at ScienceDirect

International Journal of Medical Microbiology

Hostpathogen interactions in epidermolysis bullosa patients

Magdalena M. van der Kooi-Pol a , Jos C. Duipmans b , Marcel F. Jonkman b ,

Staphylococcus aureus harmless commensal or dangerous

Corresponding author at: Department of Medical Microbiology, University of

almost all tissues and organs causing a broad range of diseases

1438-4221/$ see front matter 2013 Published by Elsevier GmbH.

of so-called community-acquired MRSA (CA-MRSA) strains has laid

within the epidermis. In junctional EB (JEB), subepidermal cleavage

Bacterial wound colonization

Fig. 2. Schematic representation of the bacterial presence in wounds. The bacterial

Colonization of patients with EB

S. aureus types are not mutually exclusive. Accordingly, we have

Staphylococcal virulence factors

exoproteome patterns as have been shown for S. aureus cells grown

that S. aureus shows major adaptive responses to different host

strongly during the course of infection in patients with bacteremia

carriers and bacteremia or furunculosis patients. Also the carriage

importantly in the context of the present review, it is currently

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